This invention relates to an intimal thickening inhibitory agent and more particularly an intimal thickening inhibitory agent comprising a 2,6-di-t-butylphenol derivative as an active ingredient.
It is known that coronary sclerosis is a primary cause of ischemic heart diseases such as angina pectoris and cardiac infarction. Narrowing of the vascular lumen resulting from arteriosclerotic thickening of the intima brings about nutrition and oxygen deficiencies in the myocardial tissues to induce the above diseases. Percutaneous transluminal coronary angioplasty (hereinafter abbreviated as xe2x80x9cPTCAxe2x80x9d) that has recently been developed as a treatment for the ischemic heart diseases such as angina pectoris and cardiac infarction is to physically dilate a blood vessel by inflating a balloon at the stenosis region of the coronary artery. However, the problem which has been recognized from the beginning of development of this treatment is that restenosis appears at the treated region within 3 to 6 months after the angioplasty at a frequency of about 40% (see Circulation, 77, pp. 361-371 (1988)).
Up to the present time, use of anticoagulants, antiplatelet agents or drugs having an inhibitory effect on proliferation of vascular smooth muscle cells has been attempted to prevent stenosis due to arteriosclerotic intimal thickening or restenosis after PTCA. Thus, an extensive research for such drug has been conducted (see, for example, JP 2-121922 A/90, JP 3-83923 A/91, JP 3-118383 A/91, JP 4-99775 A/92, JP 4-154720 A/92, JP 6-135829 A/94, JP 6-206842 A/94, JP 7-25768 A/95, JP 7-149641 A/95 and JP 7-223958 A/95). However, there has been found no drug having clinically sufficient inhibitory effect on vascular stenosis due to arteriosclerotic intimal thickening or restenosis due to intimal thickening after PTCA (see, Nihon Rinsvo, 52 (extra ed.), pp. 869-872 (1994)).
As a result of an extensive research in an attempt to solve the foregoing problem, it has been found that a compound represented by formula (1): 
wherein X represents an oxygen atom or a group of formula (2);
xe2x80x94Sxe2x80x94(O)nxe2x80x83xe2x80x83(2)
wherein n represents an integer of from 0 to 2;
R1 represents a hydrogen atom or an acyl group;
R2 represents a hydrogen atom, a lower alkyl group or a lower alkenyl group;
R3 represents a lower alkyl group; and
R4, R5, and R6, which may be the same or different, each represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, or a substituted or unsubstituted aryl group; or
R3 and R4 may be taken together to form a 5-membered ring; or
R5 and R6 may be taken together to form a cycloalkyl group or a heterocyclic ring derived from a cycloalkyl group by substituting any one or more methylene groups on the ring with oxygen atoms, sulfur atoms or alkyl-substituted nitrogen atoms;
provided that R6 is nil when R3 and R4 are taken together to form a benzofuran ring, a benzo[b]thiophene ring, a benzo[b]thiophene-1-oxide ring or a benzo[b]thiophene-1,1-dioxide ring,
exhibits an excellent inhibitory effect on proliferation of vascular smooth muscle cells as well as on intimal thickening in balloon injury models.
The fact that the compound represented by formula (1) is effective in the treatment and prevention of ischemic organopathy such as arteriosclerosis, cardiac infarction and apoplexy has already been revealed (see JP 6-206842 A/94, WO 94-08930, and WO 95-27710).
In the above formula (1), the acyl groups include an acetyl group, a formyl group, a propionyl group, a benzoyl group, a benzyloxycarbonyl group, an aminoacetyl group, an N-methylaminoacetyl group, and an N,N-dimethylaminoacetyl group. The term xe2x80x9clower alkyl groupxe2x80x9d means a straight- or branched-chain alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, a n-propyl group, an i-propyl group, a n-butyl group, a sec-butyl group, and a tert-butyl group. The term xe2x80x9clower alkenyl groupxe2x80x9d means a straight- or branched-chain alkenyl group having 2 to 6 carbon atoms, for example, a vinyl group, an allyl group, a butenyl group, and a pentenyl group.
The alkyl group represented by R4, R5, or R6 is a straight- or branched-chain alkyl group having 1 to 20 carbon atoms, for example, a methyl group, an ethyl group, a n-propyl group, an i-propyl group, a n-butyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, and a decyl group. The alkenyl group is a straight- or branched-chain alkenyl group having 2 to 20 carbon atoms, for example, a vinyl group, an allyl group, a butenyl group, a pentenyl group, a geranyl group, and a farnesyl group. The alkynyl group is a straight- or branched-chain alkynyl group having 2 to 20 carbon atoms, for example, an ethynyl group, a propynyl group, and a butynyl group. The aryl group is a monovalent substituent derived from an aromatic hydrocarbon by removing one hydrogen atom, for example, a phenyl group, a tolyl group, a xylyl group, a biphenyl group, a naphthyl group, an anthryl group, and a phenanthryl group. Substituents in the substituted alkyl, alkenyl, alkynyl or aryl group include a halogen atom, a lower alkyl group, a hydroxyl group, an amino group, an alkoxy group, an aryloxy group, a nitro group, and a trifluoromethyl group.
The 5-membered rings formed by R3 and R4 include a furan ring, a dihydrofuran ring, a thiophene ring, and a dihydrothiophene ring, which are taken together with the benzene ring to form a benzofuran ring, a dihydrobenzofuran ring, a benzo[b]thiophene ring, and a dihydrobenzothiophene ring, respectively.
The cycloalkyl group is a cycloalkyl group having 3 to 8 carbon atoms, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. The heterocyclic rings derived from the cycloalkyl group by substituting any one or more methylene groups on the ring with oxygen atoms, sulfur atoms or alkyl-substituted nitrogen atoms include, for example, a tetrahydropyranyl group.
Where X in formula (1) is an oxygen atom,
R1 is preferably a hydrogen atom, an acetyl group, a benzyloxycarbonyl group, an aminoacetyl group, an N-methylaminoacetyl group or an N,N-dimethylaminoacetyl group, particularly a hydrogen atom, an acetyl group or an N,N-dimethylaminoacetyl group;
R2 is preferably a hydrogen atom, a methyl group or a n-propyl group, particularly a hydrogen atom;
R3 and R4 are preferably taken together to form a furan ring or a dihydrofuran ring, particularly a dihydrofuran ring;
R5 is preferably a hydrogen atom, a methyl group, a n-butyl group, a n-pentyl group, a n-hexyl group or an i-amyl group, particularly a n-pentyl group; and
R6 is preferably a hydrogen atom, a methyl group, a n-butyl group, a n-pentyl group, a n-hexyl group or an i-amyl group, particularly a n-pentyl group; or
R5 and R6 are preferably taken together to form a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, or a tetrahydropyranyl group, particularly a cyclohexyl group, a cycloheptyl group, or a cyclooctyl group.
Where X in formula (1) is a group represented by formula (2):
xe2x80x94Sxe2x80x94(O)nxe2x80x83xe2x80x83(2)
wherein n is an integer of from 0 to 2,
R1 is preferably a hydrogen atom, an acetyl group, a benzyloxycarbonyl group, an aminoacetyl group, an N-methylaminoacetyl group or an N,N-dimethylaminoacetyl group, particularly a hydrogen atom, an acetyl group or an N,N-dimethylaminoacetyl group;
R2 is preferably a hydrogen atom, a methyl group or an n-propyl group, particularly a hydrogen atom;
R3 and R4 are preferably taken together to form a thiophene ring or a dihydrothiophene ring, particularly a dihydrothiophene ring;
R5 is preferably a hydrogen atom, a methyl group, a n-butyl group, a n-pentyl group, a n-hexyl group or an i-amyl group, particularly a n-pentyl group; and
R6 is preferably a hydrogen atom, a methyl group, a n-butyl group, a n-pentyl group, a n-hexyl group or an i-amyl group, particularly a n-pentyl group; or
R5 and R6 are preferably taken together to form a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, or a tetrahydropyranyl group, particularly a cyclohexyl group, a cycloheptyl group, or a cyclooctyl group; and
n is preferably 0 or 1, particularly 0.
Examples of the specific compounds used for the inhibitory agent of the present invention include 4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzofuran, 4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran, 4,6-di-t-butyl-5-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran, 4,6-di-t-butyl-2,2-diethyl-5-hydroxy-2,3-dihydrobenzofuran, 4,6-di-t-butyl-2,2-di-n-propyl-5-hydroxy-2,3-dihydrobenzofuran, 4,6-di-t-butyl-2,2-d i-n-butyl-5-hydroxy-2,3-dihydrobenzofuran, 4,6-di-t-butyl-5-hydroxy-2-octylbenzofuran, 4,6-di-t-butyl-5-hydroxy-2-octyl-2,3-dihydrobenzofuran, 2,4,6-tri-t-butyl-5-hydroxy-2,3-dihydrobenzofuran, 4,6-di-t-butyl-2,2-di-i-propyl-5-hydroxy-2,3-dihydrobenzofuran, 4,6-di-t-butyl-2,2-diphenyl-5-hydroxy-2,3-dihydrobenzofuran, 4,6-di-t-butyl-2,2-dibenzyl-5-hydroxy-2,3-dihydrobenzofuran, 4,6-di-t-butyl-2-chloromethyl-5-hydroxy-2,3-dihydrobenzofuran, 4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzofuran-2-spiro-1xe2x80x2-cyclopentane, 4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzofuran-2-spiro-1xe2x80x2-cyclohexane, 4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzofuran-2-spiro-1xe2x80x2-cycloheptane, 4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzofuran-2-spiro-1xe2x80x2-cyclooctane, 4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzofuran-2-spiro-4xe2x80x2-tetrahydropyran, 5-hydroxy-4,6-di-t-butyl-2,2-dimethyl-7-propyl-2,3-dihydrobenzofuran, 4,6-di-t-butyl-5-hydroxybenzofuran, 4,6-di-t-butyl-5-hydroxy-2-methylbenzofuran, 2,4,6-tri-t-butyl-5-hydroxybenzofuran, 2,6-di-t-butyl-3-methyl-4-propyloxyphenol, 4-allyloxy-2,6-di-t-butyl-3-methylphenol, 1,3-bis(3,5-di-t-butyl-4-hydroxy-2-methylphenoxy)propane, 4,6-di-t-butyl-2,2-di-n-pentyl-5-hydroxy-2,3-dihydrobenzofuran, 4,6-di-t-butyl-2,2-di-n-octyl-5-hydroxy-2,3-dihydrobenzofuran, 4,6-di-t-butyl-2,2-di-n-heptyl-5-hydroxy-2,3-dihydrobenzofuran, 4,6-di-t-butyl-2,2-di-n-hexyl-5-hydroxy-2,3-dihydrobenzofuran, 2,2-di-i-amyl-4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzofuran, 4,6-di-t-butyl-5-hydroxy-2-methyl-2-(4,8,12-trimethyl-trideca-3(E),7(E),11-trienyl)-2,3-dihydrobenzofuran, 4,6-di-t-butyl-5-hydroxy-2-methyl-2-(4xe2x80x2,8xe2x80x2,12xe2x80x2-trimethyltridecyl)-2,3-dihydrobenzofuran, 4,6-di-t-butyl-5-hydroxy-2-(5-hydroxy-4-methyl-3(E)-pentenyl)-2-methyl-2,3-dihydrobenzofuran, 4,6-di-t-butyl-5-hydroxy-2-hydroxymethyl-2-methyl-2,3-dihydrobenzofuran, 4,6-di-t-butyl-5-hydroxy-2,2-di-n-pentyl-2,3-dihydrobenzothiophene, 4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzothiophene, 4,6-di-t-butyl-5-hydroxy-2,2-dimethyl-2,3-dihydrobenzothiophene, 4,6-di-t-butyl-5-hydroxybenzo[b]thiophene, 4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzothiophene, 4,6-di-t-butyl-5-hydroxy-2,2-diethyl-2,3-dihydrobenzothiophene, 4,6-di-t-butyl-5-hydroxy-2,2-di-n-propyl-2,3-dihydrobenzothiophene, 4,6-di-t-butyl-5-hydroxy-2,2-di-i-propyl-2,3-dihydrobenzothiophene, 4,6-di-t-butyl-5-hydroxy-2,2-di-n-butyl-2,3-dihydrobenzothiophene, 4,6-di-t-butyl-5-hydroxy-2,2-di-i-amyl-2,3-dihydrobenzothiophene, 4,6-di-t-butyl-5-hydroxy-2,2-di-n-hexyl-2,3-dihydrobenzothiophene, 4,6-di-t-butyl-5-hydroxy-2,2-di-n-heptyl-2,3-dihydrobenzothiophene, 4,6-di-t-butyl-5-hydroxy-2,2-di-n-octyl-2,3-dihydrobenzothiophene, 4,6-di-t-butyl-5-hydroxy-2,2-diphenyl-2,3-dihydrobenzothiophene, 4,6-di-t-butyl-5-hydroxy-2,2-dibenzyl-2,3-dihydrobenzothiophene, 4,6-di-t-butyl-5-hydroxy-2-methyl-2-(4,8,12-trimethyltrideca-3(E),7(E),11-trienyl)-2,3-dihydrobenzothiophene, 4,6-di-t-butyl-5-hydroxy-2-methyl-2-(4,8,12-trimethyltridecyl)-2,3-dihydrobenzothiophene, 4,6-di-t-butyl-5-hydroxy-2-n-octyl-2,3-dihydrobenzothiophene, 2,4,6-tri-t-butyl-5-hydroxy-2,3-dihydrobenzothiophene, 4,6-di-t-butyl-5-hydroxy-2,2-dimethyl-7-n-propyl-2,3-dihydrobenzothiophene, 4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzothiophene-2-spiro-1xe2x80x2-cyclopentane, 4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzothiophene-2-spiro-1xe2x80x2-cyclohexane, 4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzothiophene-2-spiro-1xe2x80x2-cycloheptane, 4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzothiophene-2-spiro-1xe2x80x2-cyclooctane, 4,6-di-t-butyl-2-methyl-5-hydroxybenzo[b]thiophene, 2,4,6-tri-t-butyl-5-hydroxybenzo[b]thiophene, 4,6-di-t-butyl-2-octyl-5-hydroxybenzo[b]thiophene, 4,6-di-t-butyl-5-hydroxy-2-(N,N-dimethylaminomethyl)-2-methyl-2,3-dihydrobenzothiophene, 4,6-di-t-butyl-5-hydroxy-2-hydroxymethyl-2-methyl-2,3-dihydrobenzothiophene, 4,6-di-t-butyl-5-hydroxy-2-methyl-2-(4,8-dimethyl-nona-3(E),7-dienyl)-2,3-dihydrobenzothiophene, and 4,6-di-t-butyl-5-hydroxy-2-methyl-2-(4,8-dimethylnonyl)-2,3-dihydrobenzothiophene.
The compound represented by formula (1) used in the present invention is synthesized in accordance with, for example, the process described in JP 6-206842 A/94 or WO 95-27710.
The vascular intimal thickening inhibitory agent of the present invention can be used in the form of a pharmaceutical composition comprising a compound of formula (1) together with physiologically non-toxic solid or liquid pharmaceutical carrier. The pharmaceutical composition may be in a variety of dosage forms depending on the administration route. Suitable dosage forms include tablets, granules, pills, capsules, solutions, syrups, suspensions, emulsions, and injection solutions. Usual pharmaceutical carriers, such as excipient, binder, disintegrant, lubricant, coating agent, solubilizer, emulsifier, suspending agent, stabilizer, and solvents, may be used.
The compound represented by formula (1) and the above pharmaceutical composition according to the present invention can be administered by an oral or parenteral route such as intravenous injection or as a sustained release formulation or by a topical route, such as through a catheter.
The actual dosage of the compound of formula (1) to be required for inhibiting restenosis after PTCA depends on the age of the patient, the severity of the condition to be treated, the administration route, and the like. However, the effective dosage which is generally accepted will be in the range of, for example, 1 to 1000 mg, preferably 100 to 300 mg per day in the treatment of adult human. The dosage is preferably given in 1 to 3 dose administrations daily to the patient in need of such treatment.